2.1. MELANOMA
Primary malignant melanoma of the skin is the leading cause of death from any skin disease (see Fitzpatrick et al., 1983, in "Harrison's Principles of Internal Medicine," Edition, Petersdorf et al. eds., McGraw Hill, New York, pp. 836-838). Melanoma has been estimated to account for 1 percent of all skin cancers, with an incidence of approximately 4.5 in 100,000 person-years in Caucasians and 0.6 in 100,000 person years in Blacks in the U.S. (Ibid., p. 368). The incidence of melanoma is higher in light-skinned persons and increases with geographical proximity to the equator (Id.).
Because chemotherapy is frequently ineffective in treating melanoma, and because melanomas have a propensity for metastasis (Foos et al., 1983, in "Intraocular Tumors", eds. Lommatzsch et al., Springer-Verlag, Berlin pp. 51-57), early detection followed by surgical excision is a key element in successful treatment of the disease. The five-year survival decreases in proportion to the depth of tumor invasion (Id.). With less than 0.85 mm of invasion, the five year survival is about 99 percent; this drops to less than 10 percent in metastatic melanoma.
The incidence of melanoma has increased sharply over the last few decades. In the Connecticut Registry, between 1935 and 1939, the incidence of melanoma was 1.2/10.sup.5 persons/year; this increased to 4.8/10.sup.5 persons/year in 1965-1969, to 7.2/10.sup.5 persons/year in 1976-1977, and to 9/10.sup.5 persons/year in 1979-1980. By the year 2000, one in 90 Caucasians in the United States is expected to develop the disease (Rigel et al., 1987, J. Am. Acad. Dermatol. 17:1050-1053).
Melanomas are highly variable with respect to aberrant gene expression and chromosomal lesions but share a common characteristic of an acquired independence from environmental growth factors that are needed for proliferation of normal melanocytes (Halaban, 1991, Cancer Metastasis Rev. 10:129-140). In normal melanocyte proliferation as well as uncontrolled melanoma growth, receptors with tyrosine kinase activity, such as certain growth factor receptors, appear to play an important role (Id.; Becker et al., 1992, Oncogene 7:2303-2313). Various studies have suggested that a number of growth factors may be involved in melanomagenesis (Kock et al., 1991, Cancer Treat. Res. 54:41-66; Rodeck and Herlyn, 1991, Cancer Metastasis Rev. 10:89-101; Rodeck et al., 1991, J. Invest. Dermatol. 97:20-26); such growth factors include basic fibroblast growth factor (Albino et al., 1991, Cancer Res. 51:4815-4820; Rodeck and Herlyn, 1991, Cancer Metastasis Rev. 10:89-101; Dotto et al., 1989, J. Cell Biol. 109:3115-3128; contradicted by Yamanishi et al., 1992, Cancer Res. 52:5024-5029); transforming growth factors alpha and beta (Albino et al., 1991, Cancer Res. 51:4815-4820; Rodeck and Herlyn, 1991, Cancer Metastasis Rev. 10:89-101); hepatocyte growth factor/scatter factor (Halaban et al., 1992, Oncogene 7:2195-2206); tumor necrosis factor alpha and/or beta (Kirnbauer et al., 1992, J. Invest. Dermatol. 98:320-326; Krutmann et al., 1992, J. Invest. Dermatol. 98:923-928); platelet derived growth factor (Rodeck and Herlyn, 1991, Cancer Metastasis Rev. 10:89-101); and various interleukins (Kirnbauer et al., 1992, J. Invest. Dermatol. 98:320-326; partly contradicted by Lu et al., 1992, Proc. Natl. Acad. Sci. 89:9215-9219). Becker et al. (1992, Oncogene 7:2303-2313) implicates the fibroblast growth factor receptor in melanomagenesis. Other studies suggest that molecules that influence intracellular adhesion (Kirnbauer et al., J. Invest. Dermatol. 98:320-326; Krutmann et al., J. Invest. Dermatol. 98:923-928) or tissue protease activity (Mueller et al., 1992, Proc. Natl. Acad. Sci. U.S.A. 89:11832-11836) may be involved in the progression of human melanoma disease.
Thus, the literature is diverse and occasionally contradictory regarding the genesis and progression of melanoma. Furthermore, it is unclear what factors are involved in the initiation of events which lead to melanoma, as opposed to those operative in the progression of disease. A better understanding of the disease process could be obtained using a suitable animal model of human melanoma. The model could then also serve to test agents which might exacerbate the disease, and to test preventative or curative treatment strategies.